Mitochondria-targeted spin-labelled luminescent iridium anticancer complexes

Abstract

Mitochondria generate energy but malfunction in many cancer cells, hence targeting mitochondrial metabolism is a promising approach for cancer therapy. Here we have designed cyclometallated iridium(iii) complexes, containing one TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl) spin label [C₄₃H₄₃N₆O₂Ir₁·PF₆]˙ (<b>Ir-TEMPO1</b>) and two TEMPO spin labels [C₅₂H₅₈N₈O₄Ir₁·PF₆]˙ (<b>Ir-TEMPO2</b>). Electron paramagnetic resonance (EPR) spectroscopy revealed spin-spin interactions between the TEMPO units in <b>Ir-TEMPO2</b>. Both <b>Ir-TEMPO1</b> and <b>Ir-TEMPO2</b> showed bright luminescence with long lifetimes (<i>ca.</i> 35-160 ns); while <b>Ir-TEMPO1</b> displayed monoexponential decay kinetics, the biexponential decays measured for <b>Ir-TEMPO2</b> indicated the presence of more than one energetically-accessible conformation. This observation was further supported by density functional theory (DFT) calculations. The antiproliferative activity of <b>Ir-TEMPO2</b> towards a range of cancer cells was much greater than that of <b>Ir-TEMPO1</b>, and also the antioxidant activity of <b>Ir-TEMPO2</b> is much higher against A2780 ovarian cancer cells when compared with <b>Ir-TEMPO1</b>. Most notably <b>Ir-TEMPO2</b> was particularly potent towards PC3 human prostate cancer cells (IC₅₀ = 0.53 μM), being <i>ca.</i> 8× more active than the clinical drug cisplatin, and <i>ca.</i> 15× more selective towards cancer cells <i>versus</i> normal cells. Confocal microscopy showed that both <b>Ir-TEMPO1</b> and <b>Ir-TEMPO2</b> localise in the mitochondria of cancer cells.